The present invention is generally in the area of regulation of proliferation and differentiation of hematopoietic cells, and is more specifically the nucleic acid sequence encoding a protein called D4, and methods of use thereof in regulation of hematopoietic cells.
In the hematopoietic system, a common pluripotent stem cell gives rise to at least eight distinct lineages. While cells of each lineage appear to have strictly defined characteristics and function, a considerable plasticity in lineage specificity at the cellular and molecular level had been observed. For example, leukemic cells had been found to express molecular markers of more than one lineage in the same cell, as reported by Pui C. H., Raimondi S. C., Head D. R., Schell M. J., Rivera G. K., Mirro J. Jr., Crist W. M., Behm F. G. (1991) Blood 78:1327-1337; McCulloch E. A. (1983) Blood 62:1-13; Bradstock K. F., Kirk J., Grimsley P. G., Kabral A, Hughes W. G. (1989) Br J Haem 75:512; and Greaves M. F., Chan L. C., Furley A. J. W., Watt S. M., Mulgaard N. Y. (1986) Blood 67:1-6. It is unclear at the moment whether this reflects a distortion of the genetic mechanism of differentiation (McCulloch) or the normal differentiation process of stem cells (Greaves, et al.). A more dramatic example of this plasticity is the demonstration of the conversion of pre-B cells, which had undergone VDJ rearrangement, into macrophages Klinken S. P., Alexander W. S., Adams J. H. (1988) Cell 53:857-867; and Borzillo G. V., Ashmun R. A., Sherr C. J. (1990) Mol. Cell Biol. 10:2704-2174. These "de-differentiated" cells continue to maintain their immunoglobulin gene rearrangements but morphologically and functionally behave as macrophages.
It is remarkable that cells with a stably rearranged genome can convert into cells of a completely different lineage. These observations suggest that beneath the diversity some or all hematopoietic lineages continue to remain closely related. Hematopoietic cells may then be viewed not as a system of distinctly differentiated cells but as a family of related cells amongst which common features may be detected which distinguish them from other tissues.
It is surmised that there are molecules which regulate molecular events unique to all hematopoietic cells and that these molecules are likely to be important even after commitment into specific lineages.
It is therefore an object of the present invention to provide a gene, and the protein encoded thereby, which is involved in the proliferation and differentiation of hematopoietic cells.
It is a further object of the present invention to provide methods of use for the protein, and inhibition or expression of the gene for the protein, to enhance or limit hematopoietic cell proliferation and differentiation.